The genetic basis of congenital hyperinsulinism (original) (raw)
Hormone Research in Paediatrics, 2010
Background: Recessive inactivating mutations in ABCC8 and KCNJ11 (which encode the two subunits of the adenosine triphosphate-sensitive potassium (KATP) channels in β-cells) are the most common cause of medically unresponsive congenital hyperinsulinism (CHI) which requires a near-total pancreatectomy. Methods/Results: A patient born at term with marked macrosomia (5,900 g) presented at the age of 2 h with severe hyperinsulinaemic hypoglycaemia. He failed to respond to treatment with the KATP agonist, diazoxide. An 18FDOPA-PET scan showed intense diffuse uptake of 18FDOPA (consistent with diffuse disease) and genetic analysis of the ABCC8 gene confirmed a compound heterozygote missense ABCC8 mutation (R168C/S606T). However, unexpectedly in this patient the hyperinsulinaemic hypoglycaemia started to improve spontaneously at 7 weeks of age prior to planned pancreatic surgery. Conclusions: This is the first report of a patient with clinically severe autosomal-recessive diffuse CHI due t...
Paternally inherited ABCC8 mutation causing diffuse congenital hyperinsulinism
Endocrinology, Diabetes and Metabolism Case Reports, 2013
Background: Congenital hyperinsulinism (CHI) is a rare genetic disorder characterised by inappropriate insulin secretion in the face of severe hypoglycaemia. There are two histological subtypes of CHI namely diffuse and focal. Diffuse CHI is most common due to recessive mutations in ABCC8/KCNJ11 (which encode the SUR/KIR6.2 components of the pancreatic b-cell K ATP channel) whereas focal CHI is due to a paternally inherited ABCC8/KCNJ11 mutation and somatic loss of heterozygosity for the 11p allele inside the focal lesion. Fluorine-18-L-dihydroxyphenylalanine positron emission tomography/computed tomography ( 18 F-DOPA-PET/CT) is used in the pre-operative localisation of focal lesions prior to surgery. Diffuse CHI if medically unresponsive will require a near total pancreatectomy whereas focal CHI will only require a limited lesionectomy, thus curing the patient from the hypoglycaemia. Aims: To report the first case of genetically confirmed CHI in Singapore from a heterozygous paternally inherited ABCC8 mutation. Methods/Results: A term male infant presented with severe hyperinsulinaemic hypoglycaemia (HH) after birth and failed medical treatment with diazoxide and octreotide. Genetic testing (paternally inherited mutation in ABCC8/p.D1472N) suggested focal disease, but due to the unavailability of 18 F-DOPA-PET/CT to confirm focal disease, a partial pancreatectomy was performed. Interestingly, histology of the resected pancreatic tissue showed changes typical of diffuse disease. Conclusion: Heterozygous paternally inherited ABCC8/KCNJ11 mutations can lead to diffuse or focal CHI.
Familial Focal Congenital Hyperinsulinism
The Journal of Clinical Endocrinology & Metabolism, 2011
Background: Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia. Histologically, there are two subgroups, diffuse and focal. Focal CHI is a consequence of two independent events, inheritance of a paternal mutation in ABCC8/KCNJ11 and paternal uniparental isodisomy of chromosome 11p15 within the embryonic pancreas, leading to an imbalance in the expression of imprinted genes. The probability of both events occurring within siblings is rare.
Hormone Research in Paediatrics, 2010
to respond to treatment with the KATP agonist, diazoxide. An 18F DOPA-PET scan showed intense diffuse uptake of 18F DOPA (consistent with diffuse disease) and genetic analysis of the ABCC8 gene confirmed a compound heterozygote missense ABCC8 mutation (R168C/S606T). However, unexpectedly in this patient the hyperinsulinaemic hypoglycaemia started to improve spontaneously at 7 weeks of age prior to planned pancreatic surgery. Conclusions: This is the first report of a patient with clinically severe autosomal-recessive diffuse CHI due to a compound heterozygous ABCC8 mutation that has resulted in spontaneous resolution at such an early age. Compound heterozygote ABCC8 mutations result in complex interactions, and it is possible that this interaction may Abstract Background: Recessive inactivating mutations in ABCC8 and KCNJ11 (which encode the two subunits of the adenosine triphosphate-sensitive potassium (K ATP ) channels in  -cells) are the most common cause of medically unresponsive congenital hyperinsulinism (CHI) which requires a near-total pancreatectomy. Methods/Results: A patient born at term with marked macrosomia (5,900 g) presented at the age of 2 h with severe hyperinsulinaemic hypoglycaemia. He failed • Congenital hyperinsulinism due to inactivating mutations (homozygous or heterozygous) in ABCC8
Novel mutation c.597_598dup in exon 5 of ABCC8 gene causing congenital hyperinsulinism
Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 2014
Congenital hyperinsulinism (CHI), a clinically and genetically heterogeneous disease, characterized by the unregulated secretion of insulin from pancreatic b-cells, is the most common cause of persistent hypoglycemia in infancy. Early diagnosis and maintenance of normoglycaemia are essential to prevent adverse neurodevelopmental outcomes. The most common and severe forms of CHI are caused by inactivating mutations in ABCC8 and KCNJ11 genes, encoding the two subunits of the pancreatic b-cell ATP sensitive potassium channel (KATP). We report a case of neonatal CHI due to a novel homozygous recessive mutation in the ABCC8 gene.
American Journal of Clinical Pathology, 2016
Objectives: To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation. Methods: High-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly. Results: Enlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation. Conclusions: Increased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition. Congenital hyperinsulinism in infancy (CHI) is the most common cause of persistent or recurrent hypoglycemia in early childhood and infancy. CHI is broadly characterized by the inappropriate release of insulin from pancreatic b cells for the level of glycemia and is associated with hypoglycemia-induced brain injury and adverse long-term neurologic outcomes in more than one-third of cases. 1-3 The hypoglycemia can be unresponsive to diazoxide, somatostatin analogues, and other medications, necessitating partial or near-total pancreatectomy. 1-3 Defects in several genes are identifiable causes of CHI, 4-6 but for many cohorts of patients with persistent disease, the genetic basis of disease is unknown, 7-11 ranging from 18% in Saudi Arabia 12 to greater than 60% in Australia 13 and China. 14 The most common origins of drug-unresponsive disease are due to inactivating mutations in either the ABCC8 or KCNJ11 genes. These encode subunits of adenosine triphosphate (ATP)-sensitive K þ channels in b cells and result in loss of channel function, leading to inappropriate changes in the b-cell membrane potential, calcium influx, and insulin release. 15 In addition to a spectrum of severities and genetic causes, CHI also has anatomopathologic diversity, 16 which means that surgical management can be selectively deployed if affected parts of the pancreas can be identified. In patients with diffuse CHI (CHI-D), all islets throughout the pancreas are affected, 16 whereas in patients with focal CHI (CHI-F), b-cell defects are localized to a topographical region caused by hyperplasia due to the loss of maternally imprinted genes. 17 Recently, a third form of the condition has been described, accounting for approximately 10% to
Genotype and Phenotype Correlations in 417 Children With Congenital Hyperinsulinism
The Journal of Clinical Endocrinology & Metabolism, 2013
Context: Hypoglycemia due to congenital hyperinsulinism (HI) is caused by mutations in 9 genes. Objective: Our objective was to correlate genotype with phenotype in 417 children with HI. Methods: Mutation analysis was carried out for the ATP-sensitive potassium (KATP) channel genes (ABCC8 and KCNJ11), GLUD1, and GCK with supplemental screening of rarer genes, HADH, UCP2, HNF4A, HNF1A, and SLC16A1. Results: Mutations were identified in 91% (272 of 298) of diazoxide-unresponsive probands (ABCC8, KCNJ11, and GCK), and in 47% (56 of 118) of diazoxide-responsive probands (ABCC8, KCNJ11, GLUD1, HADH, UCP2, HNF4A, and HNF1A). In diazoxide-unresponsive diffuse probands, 89% (109 of 122) carried KATP mutations; 2% (2 of 122) had GCK mutations. In mutation-positive diazoxide-responsive probands, 42% were GLUD1, 41% were dominant KATP mutations, and 16% were in rare genes (HADH, UCP2, HNF4A, and HNF1A). Of the 183 unique KATP mutations, 70% were novel at the time of identification. Focal HI accounted for 53% (149 of 282) of diazoxideunresponsive probands; monoallelic recessive KATP mutations were detectable in 97% (145 of 149) of these cases (maternal transmission excluded in all cases tested). The presence of a monoallelic recessive KATP mutation predicted focal HI with 97% sensitivity and 90% specificity. Conclusions: Genotype to phenotype correlations were most successful in children with GLUD1, GCK, and recessive KATP mutations. Correlations were complicated by the high frequency of novel missense KATP mutations that were uncharacterized, because such defects might be either recessive or dominant and, if dominant, be either responsive or unresponsive to diazoxide. Accurate and timely prediction of phenotype based on genotype is critical to limit exposure to persistent hypoglycemia in infants and children with congenital HI. (J Clin Endocrinol Metab 98: E355-E363, 2013) C ongenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. The disorder represents a heterogeneous group of diseases of pancreatic insulin regulation that differ with regard to responsiveness to medical treatment with diazoxide, requirement for surgery, histopathology, and molecular etiology (1). HI is most commonly associated with inactivating mutations in one of two adjacent genes located on chromosome 11p15.1: ABCC8 and KCNJ11, encoding the sulfonylurea receptor 1 and Kir6.2 proteins, which together form the ATP-sensitive plasma membrane potassium (KATP) channel in pancreatic -cells (2-5). The loss of KATP channel activity leads to persistent membrane depolarization and insulin release, regardless of
Early human development, 2010
Congenital hyperinsulinism (CHI or HI) is a condition leading to recurrent hypoglycemia due to an inappropriate insulin secretion by the pancreatic islet beta cells. HI has two main characteristics: a high glucose requirement to correct hypoglycemia and a responsiveness of hypoglycemia to exogenous glucagon. HI is usually isolated but may be rarely part of a genetic syndrome (e.g. Beckwith-Wiedemann syndrome, Sotos syndrome etc.). The severity of HI is evaluated by the glucose administration rate required to maintain normal glycemia and the responsiveness to medical treatment. Neonatal onset HI is usually severe while late onset and syndromic HI are generally responsive to a medical treatment. Glycemia must be maintained within normal ranges to avoid brain damages, initially with glucose administration and glucagon infusion then, once the diagnosis is set, with specific HI treatment. Oral diazoxide is a first line treatment. In case of unresponsiveness to this treatment, somatostati...
Congenital hyperinsulinism: current trends in diagnosis and therapy
Orphanet Journal of Rare Diseases, 2011
Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) muta...